title: Genome-wide alteration of 5-hydroxymethylcytosine in a mouse model of fragile X-associated tremor/ataxia syndrome.
abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder in which patients carry premutation alleles of 55-200 CGG repeats in the FMR1 gene. To date, whether alterations in epigenetic regulation modulate FXTAS has gone unexplored. 5-Hydroxymethylcytosine (5hmC) converted from 5-methylcytosine (5mC) by the ten-eleven translocation (TET) family of proteins has been found recently to play key roles in neuronal functions. Here, we undertook genome-wide profiling of cerebellar 5hmC in a FXTAS mouse model (rCGG mice) and found that rCGG mice at 16 weeks showed overall reduced 5hmC levels genome-wide compared with age-matched wild-type littermates. However, we also observed gain-of-5hmC regions in repetitive elements, as well as in cerebellum-specific enhancers, but not in general enhancers. Genomic annotation and motif prediction of wild-type- and rCGG-specific differential 5-hydroxymethylated regions (DhMRs) revealed their high correlation with genes and transcription factors that are important in neuronal developmental and functional pathways. DhMR-associated genes partially overlapped with genes that were differentially associated with ribosomes in CGG mice identified by bacTRAP ribosomal profiling. Taken together, our data strongly indicate a functional role for 5hmC-mediated epigenetic modulation in the etiology of FXTAS, possibly through the regulation of transcription.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: R Craig
authors.initials: RC
authors.lastname: Street
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Zalewski
authors.forename: Jocelyn N
authors.initials: JN
authors.lastname: Galloway
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002531:Cerebellum / Q000378:metabolism; D016384:Consensus Sequence; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D013728:Terminator Regions, Genetic; D024363:Transcription Initiation Site; D014202:Tremor / Q000235:genetics* / Q000378:metabolism
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine